How pharmacokinetic and pharmacodynamic principles pave the way for optimal basal insulin therapy in type 2 diabetes

This pedagogical review illustrates the differences between pharmacokinetic (PK) and pharmacodynamic (PD) measures, using insulin therapy as the primary example. The main conclusion is that PD parameters are of greater clinical significance for insulin therapy than PK parameters. The glucose-clamp technique, the optimal method for determining insulin PD, is explained so that the reader can understand the important studies in the literature. Key glucose-clamp studies that compare two basal insulin analogues – insulin glargine and insulin detemir – to Neutral Protamine Hagedorn insulin and to each other are then presented. The review further explains how PD parameters have been translated into useful clinical concepts and simple titration algorithms for everyday clinical practice. Finally, the necessity of overcoming patient and/or physician barriers to insulin therapy and providing continuing education and training is emphasised

Simplified quantification of insulin, its synthetic analogs and C-peptide in human plasma by means of LC-HRMS.

The quantification of peptide hormones by means of liquid chromatography (LC) coupled to mass spectrometry (MS) or other techniques (e.g. immunoassays) has been a challenging task in modern analytical chemistry. Especially for insulin, its synthetic analogs, and C-peptide, reliable determinations are urgently needed due to their diagnostic value in the management of diabetes and insulin resistance and because of the illicit use of insulin as a performance-enhancing agent in professional sports or as an effective toxin in forensic toxicology. The concomitant measurement of C-peptide and insulin offers an established tool for the diagnostic workup of hypoglycemia (endogenous vs. exogenous hyperinsulinemia), characterizing hepatic insulin clearance, and the assessment of beta-cell function (insulin secretion). Thus, the present approach offers the possibility to determine human insulin and its synthetic analogs (lispro, glulisine, aspart, glargine metabolite, degludec, detemir, porcine, and bovine) and C-peptide simultaneously after sample preparation utilizing protein precipitation and a mixed-mode cation-exchange solid-phase extraction, and subsequent detection by LC-high resolution MS. The method was fully validated regarding the following parameters: specificity, limit of detection (0.2 ng/mL), limit of quantification (0.6 ng/mL), recovery (40-90%), accuracy (78-128%), linearity, precision (< 21%), carry over, robustness, and matrix effects. The proof-of-concept was shown by analyzing authentic plasma samples from adults with class II obesity and prediabetes collected in the course of an oral glucose tolerance test. All sample preparation steps were controlled by two stable isotope-labeled internal standards, namely [[2 H10 ] Leu B6, B11, B15, B17 ]-insulin, and [[13 C6 ] Leu 26, 30 ] C-peptide

Optimisation of the Investigation of Antibody-Mediated Dysglycaemia

Two rare and severe disorders of insulin action, namely insulin autoimmune syndrome (IAS) and type B insulin resistance (TB-IR), are caused by pathogenic antibodies against insulin or the insulin receptor, respectively. These may arise in isolation or may complicate management of pre-existing diabetes mellitus, and milder forms of the conditions are often suspected in patients with insulin-treated diabetes and labile glycaemic control. Antibody depletion can effectively treat either condition in many cases. This research aimed to target major limitations of existing diagnostics, specifically, that anti-insulin antibody (IA) testing alone does not establish whether antibodies alter insulin action to a clinically-significant degree, and that no clinically-accredited diagnostic test for TB-IR currently exists. An initial collaborative study examined the ability of a panel of commercial insulin assays to quantify ten different insulin preparations. Significant variability in performance of assays against animal-derived and insulin analogues was seen, with certain insulin analogues not detected at all, with important implications for the use of insulin immunoassays in insulin-treated patients. A suite of techniques for investigation of the clinical significance of IAs were then developed and assessed. In a study of five widely-used insulin immunoassays, dilution of IAS plasma led to increased insulin recovery, and polyethylene glycol (PEG) precipitation of IAS plasma decreased insulin recovery in the majority of assays. Gel filtration chromatography (GFC) discriminated high molecular weight and monomeric insulin, while ex vivo addition of exogenous insulin to plasma increased sensitivity of insulin immunocomplex detection. An observational study was performed of 7 patients, all ultimately diagnosed with IAS. IAs were measured using radioligand-binding assay and enzyme-linked immunosorbent assay (ELISA). Method comparison showed results to differ in rank order and relative magnitude. For one patient whose screening IA result was not grossly elevated using either IA assay method, immunosubtraction studies were consistent with the presence of an IgA, a class of antibody under-/not detected in the IA assays studied. Competitive radioligand-binding studies demonstrated IAs to have a range of affinities. 4 patients treated with individualised regimens of immunosuppressive therapy varied in clinical response, and 3 were managed conservatively. Plasma insulin and C-peptide measurements made using mass spectrometry demonstrated under-estimation of insulin and over-estimation of C-peptide concentration using immunoassay in IAS. An observational laboratory and clinical study was also undertaken of 30 insulin-treated patients with diabetes and unexplained labile glycaemia. IA, and plasma insulin before and after PEG precipitation, were determined. Three groups were identified: the first were ‘negative’ for actionable IA; the second had demonstrable IAs of potential significance that warrant further study; and the third included 3 patients for whom immunomodulation therapy was indicated, with 1 other patient showing marked improvement of glycaemic control with close supervision and manipulation of insulin. Finally, anti-insulin receptor antibodies were detected using a newly developed ELISA utilising Chinese hamster ovary-expressed myc-tagged wild-type human insulin receptor. ‘Proof of principle’ was demonstrated for the new assay, with clear scope established for future diagnostic development. The ability to robustly prove, or conversely to rule out, the presence, of insulin–antibody complexes and/or anti-insulin receptor antibodies is invaluable in the investigation of patients with insulin resistance and/or unexplained labile glycaemia, and may decisively alter care pathways. Knowledge gained by this research has advanced understanding of the limitations of current laboratory diagnostics, and has thereby aided clinical-decision making for affected patients.PhD was funded by a Diabetes Research and Wellness Fellowship Sutherland–Earl Clinical Fellowship (RG68554). Funding was also received from the Medical Research Council (MRC_MC_UU_ 12012/5) and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre

Starting Insulin Treatment in Type 2 Diabetes

Type 2 diabetes is a disorder of glucose metabolism characterized by chronic hyperglycemia. Initially type 2 diabetes is characterized by insulin resistance and impaired function of beta cells, leading progressively to insulin deficiency. Type 2 diabetes is treated with diet and other lifestyle changes, and with medication modulating e.g. insulin resistance, liver glucose production and insulin secretion. Injectable insulin is added to the treatment when lifestyle changes and other medication are insufficient to maintain adequate control of hyperglycemia. The aim of the treatment is to remove the symptoms of diabetes and to prevent late complications of diabetes. Insulin was traditionally started at hospital wards, but from the early 1990’s also in outpatient care. The first substudy of this thesis examined retrospectively initiation practices and how successfully insulin treatment was introduced in 1990 – 1996 in Southwestern Finland. This study aimed also at identifying the best methods of controlling plasma glucose. It showed that in the 1990’s the incidence of insulin treatment increased and was initiated more often in outpatient care than previously. The use of combination treatment also increased, first with sulfonylureas and later with metformin as the oral drug. In combination therapy the insulin dose was smaller than with insulin monotherapy. HbA1c improved similarly in middle-aged and older age groups. Weight increase associated with insulin initiation was smaller when combined with oral agents. A prospective insulin initiation study (1994 – 1998) tested the hypothesis that hyperglycemia (fasting and postprandial hyperglycemia) may affect the outcome of insulin initiation. The type of hyperglycemia was determined by the relation of fasting plasma glucose to HbA1c. Treatment was initiated with insulin Lente or human NPH insulin. In patients treated with insulin monotherapy twice daily the decline in HbA1c was markedly greater for postprandial than fasting hyperglycemia patients suggesting that hyperglycemia type has significance in the selection of the insulin regimen. Another insulin initiation study showed that patients with fasting hyperglycemia starting on insulin (2004-2005) were significantly more prone to overweight than patients with postprandial hyperglycemia. Irrespective of the insulin preparation (insulin NPH or insulin glargine), patients with fasting hyperglycemia had a greater weight increase compared to patients with postprandial hyperglycemia. Special attention should be paid to prevention of weight increase in these patients.Tyypin 2 diabetes on glukoosiaineenvaihdunnan häiriö, jossa hallitsee krooninen hyperglykemia. Sen patofysiologiaan kuuluu alkuvaiheessa insuliiniresistenssi ja beetasolujen toimintahäiriö, joka johtaa asteittain insuliininpuutokseen. Tyypin 2 diabetesta hoidetaan ruokavaliolla, muilla elämäntapamuutoksilla ja lääkityksellä, joka vaikuttaa esim. insuliiniresistenssiin, maksan glukoosintuotantoon ja insuliinineritykseen. Pistettävä insuliini liitetään hoitoon, kun elämäntapamuutokset ja muu lääkitys eivät enää riittävästi hallitse hyperglykemiaa. Hoidolla pyritään poistamaan diabeteksen oireet ja estämään taudin myöhäiskomplikaatiot. Insuliini on perinteisesti aloitettu sairaalaosastolla, mutta 1990-luvun alusta myös avohoidossa. Tämän väitöskirjan ensimmäisessä osatyössä tutkittiin retrospektiivisesti, miten insuliini oli aloitettu ja miten hoidossa oli onnistuttu Varsinais-Suomessa 1990 – 1996. Tämä tutkimus yritti lisäksi selvittää, mitkä olisivat parhaat menetelmät verenglukoosin hallinnassa. Tutkimus osoitti, että insuliinihoito lisääntyi 1990-luvulla ja sitä toteutettiin aikaisempaa useammin avohoidossa. Yhdistelmähoito myös lisääntyi. Alkuun lääkkeenä oli suun kautta sulfonyyliurea, myöhemmin metformiini. Yhdistelmähoidossa tarvittiin pienempi insuliiniannos kuin pelkkää insuliinia käyttäen. HbA1c parani yhtä paljon vanhimpien potilaiden ryhmässä kuin keski-ikäisillä. Insuliinin aloitukseen liittyi pienempi painonnousu, jos hoidossa olivat mukana oraaliset lääkkeet. Prospektiivisessa insuliininaloitustutkimuksessa (1994 – 1998) testattiin hypoteesia, jonka mukaan hyperglykemiatyyppi (paastohyperglykemia tai postprandiaalinen hyperglykemia) saattaisi vaikuttaa insuliinihoidon tuloksiin. Hyperglykemiatyyppi määritettiin laskemalla paastoglukoosin ja HbA1c:n suhde. Hoito aloitettiin joko Lente-insuliinilla tai humaani-NPH-insuliinilla. Kun potilaita hoidettiin pelkällä insuliinilla kahdella päivittäisellä annoksella, HbA1c:n lasku oli merkitsevästi parempi postprandiaalisessa hyperglykemiassa kuin paastohyperglykemiassa, mikä viittaa siihen, että hyperglykemiatyypillä on merkitystä insuliinihoitoa valittaessa. Toisen insuliinitutkimuksen, jossa (2004 – 2005) aloitettiin insuliinihoito joko NPH- tai glargiini-insuliinilla, potilastietoja analysoitaessa havaittiin, että paastohyperglykemiapotilaat olivat merkitsevästi enemmän taipuvaisia ylipainoisuuteen kuin postprandiaalihyperglykeemikot. Riippumatta käytetystä insuliinista hoito aiheutti heille suuremman painonnousun kuin prostprandiaalisessa hyperglykemiassa. Näiden potilaiden hoidossa painonnousun estämiseen tulisi kiinnittää erityistä huomiota.Siirretty Doriast

Cost-effective strategies for the long-term management of diabetes mellitus

Diabetes mellitus (DM) is a significant public health problem that afflicted approximately 29.1 million Americans in 2012 (CDC, 2014). The estimated cost of diabetes in the United States in 2012 was $245 billion, including$176 billion in direct medical costs and $69 billion in reduced productivity (ADA, 2013a). To reach a diagnosis of DM, a clinician generally relies on fasting plasma glucose (FPG), the oral glucose tolerance test (OGTT), and/or the Hemoglobin A1c (HbA1c) test (ADA, 2013b). Current noninsulin antidiabetic medications include sulfonylureas, GLP-1 analogues, DPP-4 inhibitors, biguanides, thiazolidinediones, and SGLT2 inhibitors (Kaiser & Oetjen, 2014). Insulin therapies include basal (long-acting insulin analogues), biphasic (premixed insulin analogues), prandial (short-acting insulin analogues), and basal bolus (a combination of long-acting and short-acting insulin analogues) (Esposito et al., 2012). The aim of this study is to review the existing literature on the cost effectiveness of diabetes interventions to develop a standardized protocol for early type 2 diabetes care that can be delivered through primary care providers. The substantial cost effectiveness of preventative measures, including ad campaigns and outreach programs, has already been established (Mendis & Chestnov, 2013). Screening for impaired glucose tolerance early and implementing lifestyle and pharmacological changes at an early stage are also considered cost effective approaches for the long-term management of diabetes mellitus (Gillies et al., 2008). This study utilizes six cost effectiveness analyses on both clinical and non-clinical interventions to determine a standardized protocol for screening, diagnosing, and treating DM. Noninsulin antidiabetic drugs accounted for 78.4% of the 154.4 million prescriptions for antidiabetic drugs filled in 2012 (Hampp et al., 2014). Approximately half of the noninsulin antidiabetic drugs filled in 2012 was for metformin, whereas roughly a quarter of the same category was for sulfonylureas (Hampp et al., 2014). In decreasing order, long-acting human analog insulin and fast-acting human analog insulin were the most popular insulin variants in the insulin antidiabetic drug market (Hampp et al., 2014). Of the noninsulin antidiabetic drugs, the highest proportion of diabetic patients who achieved the HbA1C target of <7% were those taking sustained release exenatide (a GLP-1 analog) (63.2%) (Esposito et al., 2012). Of the insulin varieties, the highest proportion of diabetic patients who achieved the HbA1C target of <7% were those using basal bolus insulin (50.2%) (Esposito et al., 2012). While there are some concerns about the ability of diabetic patients with chronic kidney disease to clear metformin via renal excretion, extensive clinical experience supports its use in diabetic patients with mild to moderate renal impairment (Inzucchi et al., 2014). From the cost effectiveness studies, lifestyle modification (i.e., changes in diet and exercise) beginning at any age was determined to be a cost-effective approach in preventing and treating DM and may be cost saving for adults between the age of 25 to 44 (Herman et al., 2005). Screening for DM beginning at age 45 and repeating every three years if negative provides the best balance of effectiveness and cost effectiveness (Kahn et al., 2010). As a first-line clinical intervention, metformin was established to be cost-effective as well in treating DM (but less so compared to lifestyle modification) (Herman et al., 2005). Bariatric surgery for diabetics with a BMI greater than or equal to 35 kg/m2 has also been established as cost effective (Hoerger et al., 2010). Next, in considering the ideal frequency of clinical consultations, diabetics with a stable condition (assessed as HbA1c ≤7.5%, blood pressure ≤145 mmHg, and total cholesterol ≤201 mg/dL) can safely be seen by a primary care provider every six months compared to every three months with no noticeable decline in long-term health outcomes (Wermeling et al., 2014). For cases of T2D that cannot be simply controlled with metformin, sulfonylurea has shown that it is overall more cost-effective and effective as a second-line therapy when compared to DPP-4 inhibitors and GLP-1 analogs (Zhang et al., 2014). Cost effectiveness analysis of the long-acting analogue insulin detemir across different countries reveals substantially different cost effectiveness for the medication in terms of both nominal and purchasing power terms (Home et al., 2014). The results of these studies were parsed to establish a long-term clinical protocol for primary care providers in screening, diagnosing, and treating type 2 diabetes. Future studies should focus on integrating cost effectiveness and comparative effectiveness research in implementing even more nuanced clinical decisions through a structured protocol. The cost effectiveness of existing and new interventions--both clinical and non-clinical in nature--will also need to be continuously assessed to ensure that the measurements incorporate the most accurate set of assumptions on costs and effectiveness

Clinical challenges with excipients in insulin formulations and role of concentrated insulin

Most of the insulin formulations in clinical use contain phenol, meta-cresol or both as excipients. These excipients in insulin preparations provide stability and have antimicrobial properties. However, they are reported to be associated with undesirable side-effects especially localised allergic reactions. Amount of excipients injected per unit dose of insulin is a major determining factor in causation of these reactions. This review discusses the excipients in different insulin formulations available in India with potential of precipitating undesirable effects and the use of concentrated insulins to reduce these complications. To avoid the detrimental effects associated with excipients, removal of preservatives or use of insulin preparations devoid of excipients can be an option. Besides these approaches, one approach that can be considered is the use of concentrated insulin to reduce the volume of insulin dose and thereby the excipients. Concentrated insulins address the high insulin requirements of the growing population of patients with type 2 diabetes who require higher insulin doses. Concentrated insulins help in reduction of dose volume as well as amount of excipients injected per unit dose of insulin. U200 (concentrated r-DNA Human Insulin Premix 30/70-200 IU/ml) can be advantageous with better absorption from smaller quantity injected, lesser variability in absorption, lesser pain and discomfort due to smaller quantity, lesser chances of hypoglycaemia all of which can lead to better patient compliance. Thus, concentrated insulin U200 can be one of the alternatives to prevent/reduce clinical complications with excipients in insulins

Review of Insulin Therapy In Type 2 Diabetes Mellitus Ambulatory Patients

The purposes of this study were to review utilization of insulin therapy in type 2 diabetes mellitus out patients and identify its drug related problems. The data were collected cross-sectionally with purposive sampling method in the period March 2016 until May 2016 in Outpatient Clinic Universitas Airlangga Teaching Hospital Surabaya. The results of 240 patients showed that insulin was used as monotherapy insulin in 2,9% patients; combination 1 insulin &amp; 1-4 OAD in 31,3%; basal bolus therapy 27,9%; combination basal−bolus therapy &amp; 1-3 OAD 43,9%. Based on blood glucose target achievement, only 20,8% of patients achieve the target, 75,1% failed to achieve the target and 4,1%   suffered from hypoglycemia. Drug related problems identified adverse drug reaction of antidiabetic therapy such as hypoglycemia (6.7%), nausea (3.8%), bloating (1.3%), increase of flatulency (2.9%) and inappropriate combination (0,4%). In conclusion insulin therapy was complicated and individually, most of the patients still did not reach the target and there was potential drug related problem in this patients group. So that caring from solid inter-professional health collaboration is neede

Detemir as a once-daily basal insulin in type 2 diabetes

Scott E NelsonCleveland Family Medicine, Cleveland, Mississippi, USABackground: Insulin detemir, a long-acting basal insulin analog, is labeled for once-daily or twice-daily dosing in patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. Protocols for some earlier clinical studies of detemir evaluated twice-daily dosing, which may have generated the misperception that detemir should be prescribed twice daily for most patients. This review examines pharmacokinetic and pharmacodynamic (PK/PD), observational, and controlled studies that have evaluated once-daily and twice-daily detemir in patients with T2DM to determine the efficacy and safety of once-daily dosing.Methods: PubMed was searched using the keywords &amp;ldquo;detemir,&amp;rdquo; &amp;ldquo;once daily,&amp;rdquo; &amp;ldquo;twice daily,&amp;rdquo; and &amp;ldquo;type 2 diabetes&amp;rdquo; with the limits of clinical trial, human, and English.Results: Detemir has a relatively flat time&amp;ndash;action profile and duration of action of up to 24 hours for patients with T2DM. Once-daily dosing is the most commonly used detemir regimen reported in observational studies, and controlled clinical studies indicate that once-daily dosing controls glycosylated hemoglobin when detemir is administered alone or in combination with a prandial insulin or oral antidiabetes drugs. In comparative clinical trials, detemir had a similar time&amp;ndash;action profile and duration of action to another long-acting insulin analog, glargine, with less within-subject variability. Once-daily detemir was associated with no weight gain or less weight gain than comparator regimens. For patients who had not achieved glycemic control with a basal dose of once-daily detemir, adding a prandial insulin provided better glycemic control, less postprandial hypoglycemia, and a lower total daily dose of detemir than twice-daily detemir. Involvement of a multidisciplinary team and the use of a holistic approach for the treatment of T2DM patients are recommended to achieve and maintain the best patient outcomes.Conclusion: Results from PK/PD, observational, and controlled clinical studies support a once-daily detemir regimen alone or in combination with a prandial insulin or oral antidiabetes drugs.Keywords: basal insulin, detemir, type 2 diabetes mellitus, pharmacokinetics, pharmacodynamic

Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

The brain is the primary organ that senses blood glucose levels and initiates a stress response when blood glucose levels are too low: hypoglycemia). Insulin-dependent people with Type 1 diabetes: T1DM) have an impaired ability to sense hypoglycemia and an impaired ability to activate this counterregulatory response: CRR) to hypoglycemia. As a result, T1DM are at a greater risk of experiencing insulin induced severe hypoglycemic episodes, which can result in seizures, brain damage, or even death. Since hypoglycemia is a major barrier that limits intensive blood glucose control, important research initiatives are needed to prevent or reduce the burden of hypoglycemia for people with Type 1 diabetes, specifically by defining the mechanisms and modulators of brain glucose sensing. The experiments in this thesis were designed to investigate the role and mechanism by which insulin may regulate brain glucose sensing. Recent evidence suggests that insulin acts in the brain to regulate glucose homeostasis, central nervous system: CNS) glucose sensing, and the CRR to hypoglycemia, but the site and method of CNS insulin action are still unknown. This study 1) investigated whether insulin acts on hypothalamic neurons to regulate brain glucose sensing and 2) ascertained how insulin regulates glucose sensing by evaluating its effects on key glucose sensors and CNS glucose uptake. Taking advantage of a genetic mouse model that chronically lacks CNS insulin action: the neuronal insulin receptor knockout NIRKO mouse), this report assessed whether CNS insulin signaling regulates the brain\u27s ability to detect and respond to hypoglycemia by analyzing glucose counterregulation and neuronal activation in response to hypoglycemia. Further, to clarify a mechanism of CNS insulin action, this study assessed whether insulin regulates key glucose sensors and/or CNS glucose uptake by examining the expression patterns of key glucose sensing proteins, including glucose transporters: GLUTs) and glucokinase: GK), and measuring regional brain glucose utilization. Understanding how the brain regulates the counterregulatory response to hypoglycemia is critical to devise therapies to combat severe hypoglycemia in diabetic patients. Overall, this thesis provides new insights into insulin\u27s role in the brain to regulate CNS glucose sensing and the counterregulatory response to hypoglycemia

Glucose lowering strategies with insulin

open access journalPeople with type 1 diabetes must use insulin and a large fraction of those with type 2 condition also do so. Many therefore struggle with the unpredictable balancing of insulin dose with calorie intake and utility. A healthy pancreas makes meticulous adjustment on a continuous basis that present therapeutic insulin administration cannot match. However, much progress has been made to make it simpler to inject both background and fast-acting boost insulins with a view to better mimicking normal pancreatic output. The present fast insulins are reviewed with accent on the primary amino acid structures of the biosynthetic types that diffuse more quickly than regular insulin that associates in hexamers. This makes boost doses kinetically and clinically more effective, allowing people to inject better estimated boost and corrective doses. Formulation advances are discussed for their present and potential contributions. The newer slow-acting insulins are also described and compared, their advantage also being kinetic with a lower likelihood of inducing overnight hypoglycaemia when used optimally. Finally, the appreciation of the advantages of alternative routes of administration such as oral and peritoneal are included in this review because of the possibility of altering the hepatic to peripheral ratio, the reasons for which are more effective but less obesogenic insulin activity. The logistics of oral insulin are summarised in terms of the risks to the insulin structure, the facilitation of paracellular uptake at the apical surface and the paradoxically advantageous hepatic first pass. Other non-invasive routes are also included in the review